Project Summary Alzheimer?s Disease (AD) is the most common form of dementia in humans. Despite intense research there is as yet no cure for AD and increasing incidence of AD in developed countries poses a tremendous cost to society as lifespans increase. There are two forms of AD, those that have genetic determinants and comprise approximately 5% of cases, and those that arise sporadically, particularly upon aging, and comprise the vast majority (~95%) of new AD cases diagnosed. The underlying triggers for sporadic AD are diverse and not well understood. Current therapeutic strategies are limited to those that attenuate AD symptomology without affecting the progression of the disease itself. Thus understanding the etiology of the disease is necessary to generate better therapeutics. A widely accepted hypothesis, known as the ?mitochondrial cascade hypothesis? posits that aging leads to accumulation of damaged mitochondria that produce mitochondrial reactive oxygen species (mROS), triggering progressive oxidative damage that ultimately results in development of AD. However, despite decades of study, definitive evidence for mROS or aberrant accumulation of damaged mitochondria, as a key trigger have not emerged. Our preliminary studies establish a critical role for the mitochondrial complex I assembly factor ECSIT in the regulation of mitochondrial function, mROS production, and mitochondrial quality control. Moreover, we have obtained evidence implicating dysregulation of ECSIT expression/function in AD. Therefore, we propose a series of experiments that leverage the unique expertise of the two principal investigators, and institutional capabilities, to fully characterize the role of ECSIT in neurodegeneration and AD. The proposed experiments will allow us to directly test the mitochondrial cascade hypothesis in murine models of AD and also probe the relationship between ECSIT dysregulation and the development of AD.